The overall objective of this proposal is to study the metabolism, excretion and persistence of long-acting narcotics, using methadone as a prototype agent, in tolerant humans, maintained on methadone, and in naive and tolerant animals. These studies of long-acting narcotic metabolism are to be carried out in the setting of both normal and altered physiological states. Studies will be performed out in healthy human subjects on maintenance treatment and in subjects with chronic liver disease of varying degrees of severity. Drug interactions between methadone and agents which may alter its metabolism and which are commonly used or abused, including barbiturates, estrogens and ethanol, will be studied. The findings are to be related to observed physiological effects of methadone in each of these settings. In vitro studies on the possible role of the intestine in the biotranformations of methadone are to be performed. A new application of the use of stable isotopes in human and animal metabolic research will be introduced. Pentodeuteromethadone will be used in tracer studies and stable labeled products will be measured by quadrupole chemical ionization-mass spectroscopy. Other techniques to be used include gas chromatography, thin layer and column chromatography, radioisotope studies utilizing tissue oxidation and scintillation counting, and standard mass spectroscopy.